C4A mRNA expression in PBMCs predicts the presence and severity of delusions in schizophrenia and bipolar disorder with psychosis

Altered immune function is an established finding in psychotic disorders such as schizophrenia and bipolar disorder with psychosis, though its role in their development and progression remains to be understood. Evidence suggests altered JAK-STAT1 pathway activity in peripheral blood cells from participants with schizophrenia compared to controls. Activation of this pathway leads to increased expression of complement component 4A (C4A), which has recently been implicated in schizophrenia. Here, we examine mRNA expression of C4A in peripheral blood cells from participants with schizophrenia, bipolar disorder and controls. STAT1 and IRF-1 mRNA expression are included as measures of JAK-STAT1 pathway activation in the same participants. Further, we examine the association of each genes mRNA expression with clinical symptom measures using the Positive and Negative Syndrome Scale (PANSS) and the Psychotic Symptom Rating Scale (PSYRATS). We demonstrate that C4A, STAT1 and IRF-1 mRNA expression levels are correlated across the entire sample, indicating shared transcriptional regulatory mechanisms. Further, we show that C4A mRNA expression alone is positively associated with psychotic symptomatology, specifically the presence and severity of delusions. These findings are noteworthy given recent findings that demonstrate a critical role for complement proteins in synaptic pruning, alterations of which are proposed to contribute to psychopathology in psychosis.